Transforming Growth Factor-β (TFGbeta; TGFβ (TGF-β) is a signaling molecule that mediates signal transduction into cells through binding to a TGFbeta receptor (TGFbetaR; TGFβR (TGF-βR)). TGFbeta signaling activity regulates cell differentiation and growth, the nature of its effect, i.e. as cell growth-promoter, growth-suppressor or inducer of other cell functions, being dependent on cell type (see Roberts, et al., The transforming growth factor-betas, Peptide Growth Factors and Their Receptors, Part I, ed. by Sporn, M. B. & Roberts, A. B., Springer-Verlag, Berlin, 1990, p. 419-472).
TGFbeta is produced by a wide variety of cell types, and its cognate receptors are expressed in a wide variety of organs and cells (see Shi and Massague, Cell, Volume 113, Issue 6, 13 Jun. 2003, Pages 685-700; Biol. Signals., Vol. 5, p. 232, 1996 and Pulmonary Fibrosis, Vol. 80 of Lung Biology in Health and Disease Series, ed. by Phan, et al., p. 627, Dekker, New York, 1995). TGFbeta receptors have been identified to fall into three types: TGFbetaRI (TGFβRI) (TGFbeta type I receptor (Franzen et al., Cell, Vol. 75, No. 4, p. 681, 1993; GenBank Accession No: L11695)); TGFbetaRII (TGFβRII) (TGFbeta type II receptor (Herbert et al., Cell, Vol. 68, No. 4, p. 775, 1992; GenBank Accession No: M85079)) and TGFbetaRIII (TGFbeta type III receptor (Lopez-Casillas, Cell, Vol. 67, No. 4, p. 785, 1991; GenBank Accession No: L07594)). TGFbetaRI and TGFbetaRII have been shown to be essential for the signal transduction of TGF-beta (Laiho et al., J. Biol. Chem., Vol. 265, p. 18518, 1990 and Laiho et al., J. Biol. Chem., Vol. 266, p. 9108, 1991), while TGFbetaRIII is not thought to be essential.
TGFbeta signaling is mediated through its binding to both TGFbetaRI and RII. When the ligand binds to the extracellular ligand binding domain, the two receptors are brought together, allowing RII to phosphorylate RI and begin the signaling cascade through the phosphorylation of Smad proteins (see Shi and Massague as referred to above).
Three isoforms of TGFbeta have been identified in mammals: TGFbeta1, TGFbeta2, and TGFbeta3. Each isoform is multifunctional and acts in self-regulatory feedback mechanisms to control bioavailability for developmental processes and to maintain tissue homeostasis (as reviewed in ten Dijke and Arthur, Nature Reviews, Molecular Cell Biology, Vol. 8, November 2007, p. 857-869). Levels of TFGbeta are controlled by regulation through TGFbeta expression as well as through binding to proteoglycan, i.e., the extracellular matrix (ECM).
Dysregulated TGFbeta signaling, such as excess TGFbeta signaling and high levels of bioavailable TGFbeta, is implicated in a number of pathologies, including fibroses of various tissues, such as pulmonary fibrosis and cirrhosis, chronic hepatitis, rheumatoid arthritis, ocular disorders, vascular restenosis, keloid of skin, and the onset of nephrosclerosis.
Accordingly, there is a need to provide compounds that block or disrupt TGFbeta signaling in a specific manner, such as through binding to the TGFbeta receptor II. Such compounds can be used in therapeutics.